The opioid system is composed of three families of endogenous peptides, the enkephalins, dynorphins and β-endorphin, and three homologous GPCRs, the μ opioid receptor (MOR), δ opioid receptor (DOR) and K opioid receptor (KOR) (Filizola and Devi, 2013; Cox et al.) and nociception receptors (NOP) (Lord and Waterfield, 1977; Martin and Thompson, 1976). The opioid system plays a key role in reward and motivation, regulates emotional responses and cognition, and modulates nociception, neuroendocrine physiology and autonomic functions (see Walwyn et al., 2010; Feng et al., 2012). These opioid receptors can also form homo- and heterodimeric complexes. These opioid receptors (OR) including monomer, homo- and heterodimeric complexes signal to kinase cascades and scaffold of a variety of proteins.
Opiates have been the subject of intense research since the isolation of morphine in the early 1800s. Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain exerting their effects through the activation of opioid receptors, are among the most commonly prescribed drugs in the world. Despite their efficacy and utility, side-effects greatly limit the usefulness. These side-effects include respiratory depression, constipation, drug tolerance, physical dependence, reward, and addiction.
There is a continuing need for new OR modulators for the management of pain with reduced or fewer side effects. There is also a continuing need for new OR modulators for cardioprotection and for treating cardiac disorders, analgesia, functional pain, inflammatory pain, peripherally mediated and neuropathic pain, non-somatic pain, arthritis, mental illness, cognitive disorders, depression, Parkinson's disease, locomotor disfunction, urogenital tract disorders, bladder dysfunction, overactive bladder, urinary incontinence, neurogenic bladder, psoriasis, pruritus, non-ulcerogenic dyspepisa, gastro-intestinal disorders, functional bowel disease, diarrhea, inflammatory bowel disease, irritable bowel syndrome, interstitial cystitis, sexual dysfunctions, drug addiction, alcohol addiction, drug overdose, premature ejaculation, asthma, cough, lung edema, disorders of respiratory function, respiratory depression, functional distension, disorders of motility or secretion, and for immunomodulation, inhibiting or preventing organ or skin graft rejection, or treating tumors or cancer,